Project Summary Aging is associated with impaired vascular function and increased cardiovascular disease risk, which reduces functional capacity and negatively impacts quality of life. Endurance exercise training significantly attenuates the negative effect of aging on vascular function. The immediate post-exercise period is a critical time for cardiovascular adaptations to an acute bout of exercise. Histamine H1 and H2 receptors mediate the post- exercise vasodilation response to exercise in young adults, but it is unknown whether this mechanism remains intact with aging. The effect of endurance exercise training on histaminergic regulation of post-exercise vasodilation is also unknown. Additionally, histamine-receptor activation contributes to angiogenic potential, but whether exercise-induced histamine-receptor activation increases angiogenic potential in either young or older adults is also unknown. Thus, we will test the central hypothesis that histamine-mediated post-exercise vasodilation is blunted in sedentary older adults, but maintained in older endurance-trained adults, and that this response plays a significant role mediating the angiogenic adaptation to exercise training. Using a translational approach to understand the impact of aging on histamine-receptor mediated sustained post-exercise vasodilation and angiogenic potential, we will address the aims of this proposal using both in vivo and in vitro techniques. We will use a cross-sectional, placebo-controlled study design to complete this project with four groups of subjects: young untrained, young trained, older untrained, and older trained. We will use one-legged dynamic knee extension as an exercise model to determine the magnitude of histamine receptor-mediated post-exercise vasodilation in the four groups of subjects. Additionally, interstitial skeletal muscle microdialysate from young and older sedentary adults will be collected prior to, during, and after exercise for in vitro culture with human microvascular endothelial cells (MVECs) in order to determine the angiogenic potential of histamine receptor-mediated signals released within the skeletal muscle with exercise. Activating the histaminergic signaling pathway by exercise or other countermeasures may be a novel approach to improve skeletal muscle blood flow and reduce cardiovascular disease risk in older adults.